DESCRIPTION (adapted from the application): It has been proposed that in cystic fibrosis, the defective cystic fibrosis transmembrane regulator (CFTR) gene is responsible for hypersecretion and/or malabsorption of NaCl in airway epithelia leading to marked elevations in NaCl in airway surface liquid (ASL). Previous studies from this investigative team have shown that the pro-inflammatory chemokine, IL-8, is produced by macrophages in CF at an early age thereby contributing to neutrophil accumulation in the airways. In this proposal, the investigator addresses the mechanism by which osmolality may regulate macrophage function in CF. In preliminary studies, he has shown that changes in osmolality greatly potentiate pro-inflammatory chemokine production by macrophages, as well as by potentiating monocyte apoptosis. The goals of this proposal are to investigate the mechanisms by which hyperosmolality changes monocyte and macrophage function. The investigator hypotheses that increased chemokine production will result in increased neutrophil presence in the airways, while increased monocyte apoptosis will remove an important vehicle of neutrophil clearance. These goals will be addressed by three specific aims. Specific Aim 1 will address the mechanism of potentiation of IL-8 production by modest hyperosmolality and test the hypothesis that the mechanism involves JNK activation, AP-1 transactivation, and a hyperosmolality responsive element in the IL-8 promoter. Specific Aim 2 will investigate the mechanism of increased apoptosis in the presence of modest hyperosmolality. Based on preliminary findings, the investigator hypothesizes that the mechanisms will involve concurrent activation of p38 MAP kinase and inhibition of pro-survival signals conferred by either p42 ERK and/or Akt. Specific Aim 3 will investigate the pro-inflammatory chemokine production and apoptosis in a relevant in vivo model of CF airways involving bronchial epithelial cell xenografts in nude mice using epithelial cells from normal and CF-lungs. These studies are expected to provide novel, important insights into the role of the defective CFTR in promoting pulmonary inflammation in cystic fibrosis.